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World J Hepatol. 2010 September 27; 2(9): 337–344.
Published online 2010 September 27. doi:  10.4254/wjh.v2.i9.337
PMCID: PMC2999298

Nitric oxide and cancer

Abstract

Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived physiological messenger which regulates a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. NO is synthesized by three differentially gene-encoded NO synthase (NOS) in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2) and endothelial NOS (eNOS or NOS-3). All isoforms of NOS catalyze the reaction of L-arginine, NADPH and oxygen to NO, L-citrulline and NADP. NO may exert its cellular action by cGMP-dependent as well as by cGMP-independent pathways including postranslational modifications in cysteine (S-nitrosylation or S-nitrosation) and tyrosine (nitration) residues, mixed disulfide formation (S-nitrosoglutathione or GSNO) or promoting further oxidation protein stages which have been related to altered protein function and gene transcription, genotoxic lesions, alteration of cell-cycle check points, apoptosis and DNA repair. NO sensitizes tumor cells to chemotherapeutic compounds. The expression of NOS-2 and NOS-3 has been found to be increased in a variety of human cancers. The multiple actions of NO in the tumor environment is related to heterogeneous cell responses with particular attention in the regulation of the stress response mediated by the hypoxia inducible factor-1 and p53 generally leading to growth arrest, apoptosis or adaptation.

Keywords: Nitric oxide, Cancer, Carcinogenesis

INTRODUCTION

Discovery of nitric oxide

Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived physiological messenger[1]. NO regulates a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. Ignarro et al[2] and Moncada et al[3] identified simultaneously the endothelium-derived relaxing factor (EDRF) as NO. Hibbs et al[4] demonstrated that the reaction using L-arginine as substrate results in the formation of L-citrulline and the end products, NO2-/NO3-. The 1990s brought several landmarks to the field including the molecular characterization of the NO synthase (NOS) family of enzymes[5-8], the discovery of peroxyntrite (ONOO-)[9], the importance of NO-mediated posttranslational protein modifications[10], the regulation of mitochondrial function by NO[11-14] and the chemistry of NO diffusion/reactivity[15].

Nitric oxide synthase isoenzymes

NO is synthesized by three differentially gene-encoded NOS in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2) and endothelial NOS (eNOS or NOS-3). All three isoforms share similar structures and catalytic modes, yet the mechanisms that control their activity in time and space are quite diverse. The expression of NOS-2 is induced by inflammatory stimuli while NOS-1 and NOS-3 are more or less constitutively expressed[16]. The full active NOS form requires two NOS monomers associated with two Ca2+-binding protein calmodulin (CaM). NOS contains relatively tightly-bound cofactors such as (6R)-5,6,7,8-tetrahydrobiopterin (BH4), FAD, FMN and iron protoporphyrin IX (haem) and catalyze the reaction of L-arginine, NADPH and oxygen to NO, L-citrulline and NADP[16]. The reaction is composed of two sequential steps involving the hydroxylation of guanidino nitrogen of L-arginine generating the intermediate Nω-hydroxy-L-arginine (NOHA) which is oxidized to NO and L-citrulline[17]. HB4 acts as a redox cofactor in the second reduction step and prevents the uncoupling of NOS and generation of anion superoxide (O2--). All NOSs require similar amounts of L-arginine, BH4 and NADPH for activity. NOS isoforms are differentially regulated at transcriptional, translational and post-translational levels. However, the activity of NOS-1 and NOS-3 is highly dependent upon intracellular Ca2+ concentration whereas NOS-2 forms an active complex with CaM. NOS-2 is already maximally activated by Ca2+/CaM even at basal levels of intracellular Ca2+[16]. Several inhibitory and activator phosphorylated sites in NOS-1 and NOS-3 tightly regulate their NO production[18].

The intracellular localization is relevant for the activity of NOS. It appears that there are compartments that allow full activation of NOS with free access to substrates and cofactors as well as the presence of activators[19]. In this sense, accumulating evidence indicates that NOSs are subject to specific targeting to subcellular compartments (plasma membrane, Golgi, cytosol, nucleus and mitochondria) and that this trafficking is crucial for NO production and specific posttranslational modifications of target proteins[20,21].

NITRIC OXIDE CELL SIGNALING

The biological activity of NO is classified by cGMP-dependent and cGMP-independent pathways, both attributed to physiological and pathological conditions[22-24]. cGMP-dependent protein kinases, cyclic-nucleotide-gated ion channels and cGMP-regulated phosphodiesterases mediate several cellular effects. However, during the last decade, cGMP-independent reactions have gained considerable interest. A variety of effects are achieved through its interactions with targets via redox and additive chemistry that may promote covalent modifications of proteins as well as oxidation events that do not require attachment of the NO group. In fact, NO is the prototypic redox-signaling molecule more versatile than O2-- or H2O2 and clearly better identified with redox-related modifications of intracellular proteins[25].

Nitric oxide cGMP-independent pathways

The most prominent and recognized NO reaction with thiols groups of cysteine residues is called S-nitrosylation or S-nitrosation which leads to the formation of more stable nitrosothiols[26]. However, other modifications such as disulfide, mixed disulfide formation with reduced glutathione (S-nitrosoglutathione or GSNO) or oxidation towards sulfenic acid are also important since they are reversible. Higher thiol oxidation states such as sulfinic or sulfonic acids are irreversible modifications with subsequent loss of functional control. Nitrosothiol formation can be the result of a direct reaction with NO or of an oxidative nitrosylation reaction involving the preformation of ONOO-[27]. The pattern of nitrosylated proteins is specific, probably dependent of the presence of specific consensus motifs which influence the accessibility of the thiols groups to NO[28]. Different proteins such as NMDA and ryanodine receptors, ras, caspases, glyceraldehyde-3-phosphate dehydrogenase and DNA repair proteins are widely post-translationally modified by nitrosylation[29].

Oxidative and nitrosative stress is sensed and closely associated with transcriptional regulation of multiple target genes[30]. The net effect of NO on gene regulation is variable and ranges from activation to inhibition of transcription. S-nitrosation of specific cysteines in active zinc fingers sequences in SP-1, EGR-1 and glucocorticoid receptors, induces Zn2+ release, concomitant conformational changes and reduced DNA-binding[31]. The impact of NO in other transcription factors such as NF-kB may affect at different levels such as IkB expression and stability, NF-kB activation, nuclear translocation or cysteine residue modification involving alteration of DNA binding. The administration of NO donors reduces NF-kB activation and downstream expression of anti-apoptotic gene products[32] which is relevant for NO-dependent sensitization chemotherapy-resistant tumor cells[33,34]. It now seems more certain that reducing conditions are required in the nucleus for NF-kB DNA binding whereas oxidizing conditions in the cytoplasm promote NF-kB activation[30]. AP-1 is a transcription factor that belongs to the basic leucine zipper (bZip) family in which a single cysteine residue is present that confers redox sensitivity[35]. NO, mostly by S-nitrosylation[36] and glutathiolation[37] of cysteine, inhibits c-Jun and c-Fos DNA binding in a reversible manner. p53 also binds to its specific DNA sites in a reducing environment and mutations of cysteine residues in the p53 core binding domain (loop-sheet-helix motif linked to a loop-helix motif) prevents DNA binding and p53-induced transcription[38]. HIF-1α has a single cysteine in the basic-helix-loop-helix of the carboxyl-terminal trans-activating domain which participates in protein–protein interactions that activate transcription[39]. Other transcription factors whose binding to DNA is facilitated under reducing conditions include c-Myb, USF, NFI, NF-Y, HLF, PEBP2, GABPa, TTF-1 and Pax-8[30].

The generation of O2-- and NO may lead the production of the harmful molecule ONOO-[40]. ONOO- may result in S-nitrosylation and tyrosine nitration of proteins with a concomitant change in their function[41]. The generation of ONOO- may exert a negative feedback regulation on the NO production. In this sense, the reaction of ONOO- with Akt and BH4 altered NO production generated by NOS[42,43]. Proteins that can be nitrated on tyrosine residues include actin, histone proteins, protein kinase C, prostacyclin synthase, manganese superoxide dismutase, tyrosine hydroxylase, cytochrome P450B1, transcription factor STAT1 and p53[44]. Also, different proteins appeared to be nitrated in cultured human hepatocytes[45]. Alternatively, NO may indirectly induce gene transcription via activation/modulation of signaling pathways such as mitogen-activated protein kinases (MAPK), G-proteins, Ras pathway or phosphatidylinositol-3 kinase (PI3K) pathways[46].

NITRIC OXIDE, CELL PROLIFERATION AND CANCER

Nitrogen oxide chemistry is critical in the nitrogen cycle, converting nitrate(NO3-) and nitrite (NO2-) to ammonia (NH4+), an essential component of protein synthesis as well as in the vascular tone and cell signaling regulation. However, it has also been associated to the deleterious/cytotoxic effects in air pollution, antibacterial in the preservation of food as well as the generation of carcinogenic nitrosamines[47]. In this sense, NO may participate in the induction of genotoxic lesions as well as promoting angiogenesis, tumor cell growth and invasion[48].

Participation of nitric oxide in carcinogenesis

The infectious and non-infectious generation of chronic injury and irritation initiates an inflammatory response[49]. A subsequent respiratory burst, an increased uptake of oxygen that leads to the release of free radicals from leukocytes, including activated macrophages, can damage surrounding cells. This process can drive carcinogenesis by altering targets and pathways that are crucial to normal tissue homeostasis. NO and NO-derived reactive nitrogen species induce oxidative and nitrosative stress which results in DNA damage (such as nitrosative deamination of nucleic acid bases, transition and/or transversion of nucleic acids, alkylation and DNA strand breakage) and inhibition of DNA repair enzymes (such as alkyltransferase and DNA ligase) through direct or indirect mechanisms[50]. However, the diversity of reactive species produced during chronic inflammation under different cellular microenvironments has impaired identification of a clear biomarker that identifies the involvement of a single reactive species in the carcinogenic process[51]. Chronic inflammation contributes to about one in four of all cancer cases worldwide[49]. The induction of mutations in cancer-related genes or post-translational modifications of proteins by nitration, nitrosation, phosphorylation, acetylation or polyADP-ribosylation are some key events that can increase the cancer risk. In particular, high levels of NO are genotoxic through formation of carcinogenic nitrosamines or by directly modifying DNA or DNA repair proteins. It was found that aerobic solutions of NO, NO2 and N2O3 led to deamination of nucleic acids[52]. Unlike oxidation by ONNO- or reactive oxygen species (ROS) that preferentially results in transversions, nitrosative mixtures of NO2/N2O3 mediate transitions[53]. However, NO may also influence the carcinogenesis process by alteration of cell-cycle checkpoints[54], apoptosis[55] and DNA repair[56]. NO donors sensitize tumor cells to chemotherapeutic compounds by nitrosilation of critical thiols in DNA repair enzymes in hepatoma cell line[57]. Other studies have demonstrated increased susceptibility to chemotherapy to cisplatin[58] and melphalan[59] by NO donors in different cell lines. These results implied substantial modification of key biological target(s) including DNA repair proteins and transcription factor known to be inhibited by NO.

Cell signaling of NO in carcinogenesis

It is difficult to identify the specific role of NO in carcinogenesis because it is dependent on its concentration, interaction with other free radicals, metal ions and proteins, and the cell type and the genetic background that it targets. The expression of NOS-2 has been found to be increased in a variety of human cancers[60-62]. However, NOS-3 has also been suggested to modulate different cancer-related events (angiogenesis, apoptosis, cell cycle, invasion and metastasis)[63]. NO can both cause DNA damage and protect from cytotoxicity, can inhibit and stimulate cell proliferation and can be both pro- and anti-apoptotic[64-67]. Lancaster and Xie[68] suggest that the multiple actions of NO in the tumor environment are related to its chemical (post-translational-related modifications) and biological heterogeneity (cellular production, consumption and responses). However, one of the critical insights into this dichotomy may be the regulation by NO of the stress response mediated by the hypoxia inducible factor-1 (HIF-1)[69] and p53[70] generally leading to growth arrest, apoptosis or adaptation[71].

Nitric oxide and p53

The biological outcomes of p53 activity include apoptosis, inhibition of cell cycle progression, senescence, differentiation and accelerated DNA repair. The types of stress that promote p53 activation include many conditions associated with cancer initiation and progression such as direct DNA damage, chromosomal aberrations, illegitimate activation of oncogenes, hypoxia, telomere shortening etc. p53 is found at very low steady state in non stress conditions by the mouse double minute (Mdm2, the human orthologue form is named Hdm2) protein[72]. Mdm2 displays an E3 ubiquitin ligase activity towards p53 for ubiquitin-dependent proteasomal degradation, although non-proteasomal mechanisms for p53 degradation may also play a significant role under certain circumstances[73]. The induction of cell death or antitumoral properties of NO has been extensively related to nuclear p53 accumulation[74-77]. NO donors induce p53 accumulation and apoptosis through JNK-1/2, but not ERK1/2 or p38, activation in RAW 264.7 macrophages[78]. A peptide corresponding to the JNK binding site on p53 protein efficiently blocks its ubiquitination and consequently increases p53 half-life[79]. The nuclear accumulation of p53 is mainly regulated by posttranslational modifications by phosphorylation[80] or tyrosine nitration[81]. S-nitrosoglutathione and NO donors prevent poly-ubiquitinated-dependent p53 degradation by proteasome which it is antagonized by reducing agents[82]. Ubiquitin-activating enzyme (E1), a key component of ubiquitinization process, has a cysteine residue that is S-nitrosylated by NO donors[83].

The overexpression of NOS-2 reduced in vitro cell proliferation[84-86] and in vivo tumor progression in xenograft experimental models[84,86] using different carcinoma cell lines. Le et al[87] have recently shown that NOS-2 overexpression exerts antitumor activity in vitro and in vivo dose dependently, regardless of its up-regulation of protumor factors. Also, NOS-2-derived NO suppresses lymphomagenesis even in a p53-/- back-ground by promoting apoptosis and decreasing tumor cell proliferation[88]. NOS-2 overexpression has also been shown to induce radiosensitization through p53 accumulation in in vitro and in vivo xenograft models[89,90]. Furthermore, wild-type p53-induced transrepression of NOS-2 provides a protective mechanism against prolonged exposure to pathological conditions of NO[75,91]. The frequency of p53 mutations occurs in about 50% of all human tumors suggesting that can be an early event in the process of hepatocellular carcinogenesis[92,93]. The expression of NOS-2 has been associated with increased expression of p53 mutated isoforms in liver sections from patients with hemochromatosis and Wilson diseases[94], ulcerative colitis[95], colon cancer[96] and stomach, brain and breast cancers[60,62,97]. Ambs et al[84] have observed that NOS-2 overexpression in cells with mutated p53 accelerated tumor growth, increased vascular endothelial growth factor (VEGF) expression and neovascularization. These studies indicate that exposure of cells to high levels of NO and its derivatives during chronic inflammation in the absence of wild-type p53, and therefore the negative NOS-2 regulation, may increase the susceptibility to cancer. Therefore, loss of functional p53 may lead to a reduction of NO sensitivity and transfer to other stress survival response such as HIF-1 that may promote a selective tumoral growth advantage. However, recent study has shown that NOS-2 overexpression abrogated the growth of various human tumor cells with different p53 functional status (wild-type, mutated and gene loss)[87]. The contradictory results among studies showing the potential role of p53 in high NO production may be explained by the different overall genetic background of tumoral cell lines as well as the stromal cell-derived NO in xenograft models that may modulate the response of surrounding tumor cells.

Nitric oxide and HIF-1

NO has also revealed an impact on the redox-sensitive target HIF-1. HIF-1 is predominantly active under hypoxic conditions because the HIF-1α subunit is rapidly degraded in normoxic conditions by proteasomal degradation[98]. Different genes involved in erythropoiesis and iron metabolism (erythropoietin or transferrin), glucose/energy metabolism (glucose transporters), cell proliferation/viability decisions (transforming growth factor-β), vascular development/remodeling and/or vasomotor tone (VEGF or NOS-2) contain HRE (hypoxia responsive element)[99]. HIF-1α is overexpressed as a result of intratumoral hypoxia and/or genetic alterations affecting key oncogenes and tumor suppressor genes in human cancer[100]. Different signals other than hypoxia such as growth factors, reactive oxygen species, cytokines, NO and/or NO-derived species participate in hypoxic signaling[101]. NO, through cGMP-dependent pathways, regulates different modifications during drosophila development in oxygen deprivation conditions[102]. However, thiol groups in HIF-1 or the proteins that are involved in the regulation of HIF-1 are also potential targets for post-translational modifications by NO. GSNO or selected NO donors enhance S-nitrosylation of propyl hydroxylase which lead to HIF-1α accumulation[103,104] and HIF-1 DNA-binding activity in cell systems[105]. However, small NO concentrations induce a faster but transient HIF-1α accumulation than higher doses of the same donor[106]. NO-related HIF-1 activation mediates up-regulation of VEGF expression in normoxic human glioblastoma and hepatoma cells[107]. Different studies have also shown that phosphorylation mechanism by PI3K/Akt pathway is also involved in GSNO-induced HIF-1 accumulation[108].

As described above, HIF-1 is predominantly active under hypoxic conditions in which the generation of oxygen species, specifically H2O2, is supposed to attenuate HIF-1 activation. Similarly, the redox cycler DMNQ (2,3-dimethoxy-1,4-naphthoquinone) generating O2-- and/or H2O2 (derived from superoxide dismutase-triggered conversion of O2-- to H2O2) attenuated NO-derived reactive nitrogen species-elicited HIF-1α accumulation[108]. The attenuation by NO of hypoxia-evoked reporter gene activation has been extended to several genes such as insulin-like growth factor binding protein (IGFBP-1), endothelin-1 and VEGF[101]. In this condition, NO has been shown to prevent HIF-1 accumulation in Hep3B and PC-12 cells which it reduced by addition of a lipophilic glutathione analog or ONOO- scavenger[109]. If indeed the steady state of O2-- increases under hypoxia, it may be hypothesized that hypoxia in the presence of NO-derived reactive nitrogen species delivery promotes formation to the strong oxidant ONOO-. ONOO- in turn may not only oxidize reduced glutathione but also damage mitochondria. The differential behavior of NO in normoxic and hypoxic conditions may also be related to its capacity to regulated mitochondrial oxidative phosphorylation which may limit ROS generation and HIF-1 accumulation in hypoxic conditions[110]. In addition, the interference of NO signaling by mitochondrial O2-- generation can be rationalized by the diffusion-controlled radical interaction which may redirect signaling qualities of NO towards other species, i.e. ONOO- that may not share the ability to stabilize HIF-1α. Hypoxic intracellular environment is characterized by a complex network of radical pattern generation that in conjunction with variable amounts of defense-systems may reveal a variable HIF-response to NO.

CONCLUSION

Different studies have shown that increased and continuous NO production plays a pivotal role in the regulation of carcinogenic process. The alteration of redox status and transcriptional pattern modifications induced by NO in tumoral cells increase cell death and exerts antineoplastic properties. In this sense, more studies should be done in order to identify the temporal, spatial and concentration-dependent intra- and extra-cellular NO generation that exerts its maximum antitumoral activity either as monotherapy or combined treatment with chemotherapy.

Acknowledgments

We thank the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by “Carlos III” Health Institute for its support to the development of the Liver Research Unit.

Footnotes

Peer reviewer: Julia Peinado Onsurbe, Assistant Professor, Department of Biochemistry and Molecular Biiology, Faculty of Biology, University of Barcelona, Avda Diagonal 645, Barcelona 08028, Spain

S- Editor Zhang HN L- Editor Roemmele A E- Editor Liu N

References

1. Lancaster JR Jr. A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide. 1997;1:18–30. [PubMed]
2. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA. 1987;84:9265–9269. [PubMed]
3. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526. [PubMed]
4. Hibbs JB Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987;235:473–476. [PubMed]
5. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991;351:714–718. [PubMed]
6. Lamas S, Marsden PA, Li GK, Tempst P, Michel T. Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA. 1992;89:6348–6352. [PubMed]
7. Lyons CR, Orloff GJ, Cunningham JM. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem. 1992;267:6370–6374. [PubMed]
8. Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992;256:225–228. [PubMed]
9. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990;87:1620–1624. [PubMed]
10. Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 1992;258:1898–1902. [PubMed]
11. Bolaños JP, Peuchen S, Heales SJ, Land JM, Clark JB. Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J Neurochem. 1994;63:910–916. [PubMed]
12. Brown GC, Cooper CE. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett. 1994;356:295–298. [PubMed]
13. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett. 1994;345:50–54. [PubMed]
14. Schweizer M, Richter C. Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension. Biochem Biophys Res Commun. 1994;204:169–175. [PubMed]
15. Lancaster JR Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA. 1994;91:8137–8141. [PubMed]
16. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001;357:593–615. [PubMed]
17. Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S. Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem. 2004;279:27257–27562. [PubMed]
18. Church JE, Fulton D. Differences in eNOS activity because of subcellular localization are dictated by phosphorylation state rather than the local calcium environment. J Biol Chem. 2006;281:1477–1488. [PubMed]
19. Boo YC, Kim HJ, Song H, Fulton D, Sessa W, Jo H. Coordinated regulation of endothelial nitric oxide synthase activity by phosphorylation and subcellular localization. Free Radic Biol Med. 2006;41:144–153. [PubMed]
20. Oess S, Icking A, Fulton D, Govers R, Müller-Esterl W. Subcellular targeting and trafficking of nitric oxide synthases. Biochem J. 2006;396:401–409. [PubMed]
21. Iwakiri Y, Satoh A, Chatterjee S, Toomre DK, Chalouni CM, Fulton D, Groszmann RJ, Shah VH, Sessa WC. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. Proc Natl Acad Sci USA. 2006;103:19777–19782. [PubMed]
22. Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994;78:931–936. [PubMed]
23. Schmidt HH, Walter U. NO at work. Cell. 1994;78:919–925. [PubMed]
24. Friebe A, Koesling D. Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res. 2003;93:96–105. [PubMed]
25. Stamler JS, Hausladen A. Oxidative modifications in nitrosative stress. Nat Struct Biol. 1998;5:247–249. [PubMed]
26. Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol. 2001;3:193–197. [PubMed]
27. Espey MG, Thomas DD, Miranda KM, Wink DA. Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide. Proc Natl Acad Sci USA. 2002;99:11127–11132. [PubMed]
28. Hess DT, Matsumoto A, Nudelman R, Stamler JS. S-nitrosylation: spectrum and specificity. Nat Cell Biol. 2001;3:E46–E49. [PubMed]
29. Govers R, Oess S. To NO or not to NO: 'where?' is the question. Histol Histopathol. 2004;19:585–605. [PubMed]
30. Marshall HE, Merchant K, Stamler JS. Nitrosation and oxidation in the regulation of gene expression. FASEB J. 2000;14:1889–1900. [PubMed]
31. Kröncke KD, Carlberg C. Inactivation of zinc finger transcription factors provides a mechanism for a gene regulatory role of nitric oxide. FASEB J. 2000;14:166–173. [PubMed]
32. Bonavida B, Baritaki S, Huerta-Yepez S, Vega MI, Chatterjee D, Yeung K. Novel therapeutic applications of nitric oxide donors in cancer: roles in chemo- and immunosensitization to apoptosis and inhibition of metastases. Nitric Oxide. 2008;19:152–157. [PubMed]
33. Huerta-Yepez S, Vega M, Jazirehi A, Garban H, Hongo F, Cheng G, Bonavida B. Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-kappa B and inhibition of Bcl-xl expression. Oncogene. 2004;23:4993–5003. [PubMed]
34. Jazirehi AR, Bonavida B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene. 2005;24:2121–2143. [PubMed]
35. Abate C, Patel L, Rauscher FJ 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990;249:1157–1161. [PubMed]
36. Nikitovic D, Holmgren A, Spyrou G. Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteine residues in Jun and Fos. Biochem Biophys Res Commun. 1998;242:109–112. [PubMed]
37. Klatt P, Molina EP, Lamas S. Nitric oxide inhibits c-Jun DNA binding by specifically targeted S-glutathionylation. J Biol Chem. 1999;274:15857–15864. [PubMed]
38. Rainwater R, Parks D, Anderson ME, Tegtmeyer P, Mann K. Role of cysteine residues in regulation of p53 function. Mol Cell Biol. 1995;15:3892–3903. [PMC free article] [PubMed]
39. Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 1999;18:1905–1914. [PubMed]
40. Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991;266:4244–4250. [PubMed]
41. Hanafy KA, Krumenacker JS, Murad F. NO, nitrotyrosine, and cyclic GMP in signal transduction. Med Sci Monit. 2001;7:801–819. [PubMed]
42. Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA. Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Bio lChem. 2002;277:32552–32557. [PubMed]
43. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003;278:22546–22554. [PubMed]
44. Ischiropoulos H. Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun. 2003;305:776–783. [PubMed]
45. Rodriguez-Ariza A, Lopez-Sanchez LM, Gonzalez R, Corrales FJ, Lopez P, Bernardos A, Muntane J. Altered protein expression and protein nitration pattern during d-galactosamine-induced cell death in human hepatocytes: a proteomic analysis. Liver Int. 2005;25:1259–1269. [PubMed]
46. Lander HM. An essential role for free radicals and derived species in signal transduction. FASEB J. 1997;11:118–124. [PubMed]
47. Magee PN. Nitrosamines and human cancer: introduction and overview. Eur J Cancer Prev. 1996;5 Suppl 1:7–10. [PubMed]
48. Lala PK, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol. 2001;2:149–156. [PubMed]
49. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867. [PMC free article] [PubMed]
50. Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer. 2006;6:521–534. [PubMed]
51. Hofseth LJ, Hussain SP, Wogan GN, Harris CC. Nitric oxide in cancer and chemoprevention. Free Radic Biol Med. 2003;34:955–968. [PubMed]
52. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991;254:1001–1003. [PubMed]
53. Wink DA, Ridnour LA, Hussain SP, Harris CC. The reemergence of nitric oxide and cancer. Nitric Oxide. 2008;19:65–67. [PMC free article] [PubMed]
54. Pervin S, Singh R, Chaudhuri G. Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): potential role of cyclin D1. Proc Natl Acad Sci USA. 2001;98:3583–3588. [PubMed]
55. Melino G, Bernassola F, Knight RA, Corasaniti MT, Nistico G, Finazzi-Agro A. S-nitrosylation regulates apoptosis. Nature. 1997;388:432–433. [PubMed]
56. Jaiswal M, LaRusso NF, Nishioka N, Nakabeppu Y, Gores GJ. Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res. 2001;61:6388–6393. [PubMed]
57. Laval F, Wink DA. Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase. Carcinogenesis. 1994;15:443–447. [PubMed]
58. Wink DA, Cook JA, Christodoulou D, Krishna MC, Pacelli R, Kim S, DeGraff W, Gamson J, Vodovotz Y, Russo A, et al. Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin. Nitric Oxide. 1997;1:88–94. [PubMed]
59. Cook JA, Krishna MC, Pacelli R, DeGraff W, Liebmann J, Mitchell JB, Russo A, Wink DA. Nitric oxide enhancement of melphalan-induced cytotoxicity. Br J Cancer. 1997;76:325–334. [PMC free article] [PubMed]
60. Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S. Nitric oxide synthase activity in human breast cancer. Br J Cancer. 1995;72:41–44. [PMC free article] [PubMed]
61. Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res. 1998;58:334–341. [PubMed]
62. Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA, Ziche M. Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst. 1998;90:587–596. [PubMed]
63. Ying L, Hofseth LJ. An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res. 2007;67:1407–1410. [PubMed]
64. Ulibarri JA, Mozdziak PE, Schultz E, Cook C, Best TM. Nitric oxide donors, sodium nitroprusside and S-nitroso-N-acetylpencillamine, stimulate myoblast proliferation in vitro. In Vitro Cell Dev Biol Anim. 1999;35:215–218. [PubMed]
65. Wink DA, Cook JA, Pacelli R, DeGraff W, Gamson J, Liebmann J, Krishna MC, Mitchell JB. The effect of various nitric oxide-donor agents on hydrogen peroxide-mediated toxicity: a direct correlation between nitric oxide formation and protection. Arch Biochem Biophys. 1996;331:241–248. [PubMed]
66. Heller R, Polack T, Gräbner R, Till U. Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. Atherosclerosis. 1999;144:49–57. [PubMed]
67. Siendones E, Fouad D, Mohamed Kamal ElSaid A-E, Quintero A, Barrera P, Muntane J. Role of nitric oxide in D-galactosamine-induced cell death and its protection by PGE(1) in cultured hepatocytes. Nitric Oxide. 2003;8:133–143. [PubMed]
68. Lancaster JR Jr, Xie K. Tumors face NO problems? Cancer Res. 2006;66:6459–6462. [PubMed]
69. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003;278:19575–19578. [PubMed]
70. Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431–442. [PubMed]
71. Brüne B, von Knethen A, Sandau KB. Transcription factors p53 and HIF-1alpha as targets of nitric oxide. Cell Signal. 2001;13:525–533. [PubMed]
72. Michael D, Oren M. The p53 and Mdm2 families in cancer. Curr Opin Genet Dev. 2002;12:53–59. [PubMed]
73. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25–27. [PubMed]
74. Hofseth LJ, Saito S, Hussain SP, Espey MG, Miranda KM, Araki Y, Jhappan C, Higashimoto Y, He P, Linke SP, et al. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA. 2003;100:143–148. [PubMed]
75. Forrester K, Ambs S, Lupold SE, Kapust RB, Spillare EA, Weinberg WC, Felley-Bosco E, Wang XW, Geller DA, Tzeng E, et al. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. Proc Natl Acad Sci USA. 1996;93:2442–2447. [PubMed]
76. Messmer UK, Brune B. Nitric oxide-induced apoptosis: p53-dependent and p53-independent signalling pathways. Biochem J. 1996;319:299–305. [PubMed]
77. Ho YS, Wang YJ, Lin JK. Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinog. 1996;16:20–31. [PubMed]
78. Callsen D, Brüne B. Role of mitogen-activated protein kinases in S-nitrosoglutathione-induced macrophage apoptosis. Biochemistry. 1999;38:2279–2286. [PubMed]
79. Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 1998;12:2658–2663. [PubMed]
80. Gu M, Brecher P. Nitric oxide-induced increase in p21(Sdi1/Cip1/Waf1) expression during the cell cycle in aortic adventitial fibroblasts. Arterioscler Thromb Vasc Biol. 2000;20:27–34. [PubMed]
81. Chazotte-Aubert L, Hainaut P, Ohshima H. Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells. Biochem Biophys Res Commun. 2000;267:609–613. [PubMed]
82. Glockzin S, von Knethen A, Scheffner M, Brune B. Activation of the cell death program by nitric oxide involves inhibition of the proteasome. J Biol Chem. 1999;274:19581–19586. [PubMed]
83. Kitagaki J, Yang Y, Saavedra JE, Colburn NH, Keefer LK, Perantoni AO. Nitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53. Oncogene. 2009;28:619–624. [PMC free article] [PubMed]
84. Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, Tzeng EE, Geller DA, Billiar TR, Harris CC. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med. 1998;4:1371–1376. [PubMed]
85. Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S. Roles of nitric oxide in tumor growth. Proc Natl Acad Sci USA. 1995;92:4392–4396. [PubMed]
86. Xie K, Huang S, Dong Z, Juang SH, Gutman M, Xie QW, Nathan C, Fidler IJ. Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells. J Exp Med. 1995;181:1333–1343. [PMC free article] [PubMed]
87. Le X, Wei D, Huang S, Lancaster JR Jr, Xie K. Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. Proc Natl Acad Sci USA. 2005;102:8758–8763. [PubMed]
88. Hussain SP, Trivers GE, Hofseth LJ, He P, Shaikh I, Mechanic LE, Doja S, Jiang W, Subleski J, Shorts L, et al. Nitric oxide, a mediator of inflammation, suppresses tumorigenesis. Cancer Res. 2004;64:6849–6853. [PubMed]
89. Wang Z, Cook T, Alber S, Liu K, Kovesdi I, Watkins SK, Vodovotz Y, Billiar TR, Blumberg D. Adenoviral gene transfer of the human inducible nitric oxide synthase gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity. Cancer Res. 2004;64:1386–1395. [PubMed]
90. Cook T, Wang Z, Alber S, Liu K, Watkins SC, Vodovotz Y, Billiar TR, Blumberg D. Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53. Cancer Res. 2004;64:8015–8021. [PubMed]
91. Ambs S, Ogunfusika MO, Merriam WG, Bennett WP, Billiar TR, Harris CC. Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. Proc Natl Acad Sci USA. 1998;95:8823–8828. [PubMed]
92. Oren M. Regulation of the p53 tumor suppressor protein. J Biol Chem. 1999;274:36031–36034. [PubMed]
93. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–4878. [PubMed]
94. Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, et al. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA. 2000;97:12770–12775. [PubMed]
95. Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 2000;60:3333–3337. [PubMed]
96. Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Harrington AM, Shields PG, Felley-Bosco E, Hussain SP, Harris CC. Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst. 1999;91:86–88. [PubMed]
97. Ellie E, Loiseau H, Lafond F, Arsaut J, Demotes-Mainard J. Differential expression of inducible nitric oxide synthase mRNA in human brain tumours. Neuroreport. 1995;7:294–296. [PubMed]
98. Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem. 1999;274:6519–6525. [PubMed]
99. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16:1151–1162. [PubMed]
100. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 2002;8:S62–S67. [PubMed]
101. Brüne B, Zhou J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor-1alpha (HIF-1alpha) Curr Med Chem. 2003;10:845–855. [PubMed]
102. Wingrove JA, O'Farrell PH. Nitric oxide contributes to behavioral, cellular, and developmental responses to low oxygen in Drosophila. Cell. 1999;98:105–114. [PMC free article] [PubMed]
103. Sumbayev VV, Budde A, Zhou J, Brüne B. HIF-1 alpha protein as a target for S-nitrosation. FEBS Lett. 2003;535:106–112. [PubMed]
104. Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell. 2003;14:3470–3781. [PMC free article] [PubMed]
105. Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. Mol Pharmacol. 2000;58:1197–1203. [PubMed]
106. Sandau KB, Fandrey J, Brüne B. Accumulation of HIF-1alpha under the influence of nitric oxide. Blood. 2001;97:1009–1015. [PubMed]
107. Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D'Acquisto F, Makuuchi M, Esumi H. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem. 2001;276:2292–2298. [PubMed]
108. Sandau KB, Zhou J, Kietzmann T, Brüne B. Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem. 2001;276:39805–39811. [PubMed]
109. Agani FH, Puchowicz M, Chavez JC, Pichiule P, LaManna J. Role of nitric oxide in the regulation of HIF-1alpha expression during hypoxia. Am J Physiol Cell Physiol. 2002;283:C178–C186. [PubMed]
110. Moncada S, Erusalimsky JD. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol. 2002;3:214–220. [PubMed]

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